Derepression

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In genetics and cell biology, repression is a mechanism often used to decrease or inhibit the expression of a gene. Removal of repression is called derepression. This mechanism may occur at different stages in the expression of a gene, with the result of increasing the overall RNA or protein products. Dysregulation of derepression mechanisms can result in altered gene expression patterns, which may lead to negative phenotypic consequences such as disease.

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Derepression of transcription

Transcription can be repressed in a variety of ways, and therefore can be derepressed in different ways as well. A common mechanism is allosteric regulation. This is when a substrate binds a repressor protein and causes it to undergo a conformational change. If the repressor is bound upstream of a gene, such as in an operator sequence, then it would be repressing the gene's expression. This conformational change would take away the repressor’s ability to bind DNA, thus removing its repressive effect on transcription. [1]

Another form of transcriptional derepression uses chromatin remodeling complexes. For transcription to occur, RNA polymerase needs to have access to the promoter sequence of the gene or it cannot bind the DNA. Sometimes these sequences are wrapped around nucleosomes or are in condensed heterochromatin regions, and are therefore inaccessible. Through different chromatin remodeling mechanisms these promoter sequences can become accessible to the RNA polymerase, and transcription becomes derepressed. [2]

Transcriptional derepression may also occur at the level of transcription factor activation. Certain families of transcription factors are non-functional on their own because their active domains are blocked by another part of the protein. [3] Substrate binding to this second, regulatory domain causes a conformational change in the protein to allows access to the active domain. [3] This lets the transcription factor bind to DNA and serve its function, thus derepressing the transcription factor.

Derepression of translation

Derepression of translation increases protein production without altering the levels of mRNA in the cell. miRNAs are a common mechanism of translation repression, binding to the mRNA through complementary base pairing to silence them. [4] Certain RNA binding proteins have been shown to target untranslated regions of the mRNAs and upregulate the translation initiation rates by alleviating the repressive miRNA effects. [5]

Example of derepression

Auxin signalling

An example is the auxin mediated derepression of the auxin response factor family of transcription factors in plants. These auxin response factors are repressed by Aux/IAA repressors. In the presence of auxin, these Aux/AII proteins undergo ubiquitination and are then degraded. [6] [7] This derepresses the auxin response factors so they may carry out their functions in the cell.

Altered derepression causing diseases

Familial Alzheimer’s disease

Alzheimer’s is a neurodegenerative disease involving progressive memory loss and other declines in brain function. One common cause of familial Alzheimer’s is mutation in the PSEN1 gene. [8] This gene encodes a protein that cleaves certain intracellular peptides which, once free in the cytoplasm, promote CBP degradation. Mutations in PSEN1 decrease its production or ability to cleave proteins. This derepresses the CBP proteins, and allows them to perform their function of upregulating transcription of their target genes. [8]

Rett syndrome

Rett syndrome is a neurodevelopmental disorder involving deterioration of learned language and motor skills, autism, and seizures starting in infancy. Many cases of Rett syndrome are associated with mutations in MECP2 , a gene encoding a transcriptional repressor. [8] Mutations in this gene decrease the levels of MeCP2 binding to different promoter sequences, resulting in their overall derepression. The increased expression of these MeCP2 regulated genes in neurons contribute to the Rett syndrome phenotype. [8] [9]

Beckwith-Wiedemann syndrome

This syndrome is associated with increased susceptibility to tumors and growth abnormalities in children. A common cause of this syndrome is a mutation in an imprint control region near the Igf2 gene. [9] This imprint control region is normally bound by an insulator on the maternal allele, which represses an enhancer from acting on the Igf2 gene. This insulator is absent on the paternal allele and allows it access to the gene. Mutations in this imprint control region inhibit the insulator from binding, which derepresses enhancer activity on the maternal Igf2 gene. This abnormal derepression and increase in gene expression can result in Beckwith-Wiedemann syndrome. [9]

Related Research Articles

Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in reinforcing the DNA during cell division, preventing DNA damage, and regulating gene expression and DNA replication. During mitosis and meiosis, chromatin facilitates proper segregation of the chromosomes in anaphase; the characteristic shapes of chromosomes visible during this stage are the result of DNA being coiled into highly condensed chromatin.

<span class="mw-page-title-main">Promoter (genetics)</span> Region of DNA encouraging transcription

In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of itself, such as tRNA or rRNA. Promoters are located near the transcription start sites of genes, upstream on the DNA . Promoters can be about 100–1000 base pairs long, the sequence of which is highly dependent on the gene and product of transcription, type or class of RNA polymerase recruited to the site, and species of organism.

<span class="mw-page-title-main">Transcription factor</span> Protein that regulates the rate of DNA transcription

In molecular biology, a transcription factor (TF) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The function of TFs is to regulate—turn on and off—genes in order to make sure that they are expressed in the desired cells at the right time and in the right amount throughout the life of the cell and the organism. Groups of TFs function in a coordinated fashion to direct cell division, cell growth, and cell death throughout life; cell migration and organization during embryonic development; and intermittently in response to signals from outside the cell, such as a hormone. There are 1500-1600 TFs in the human genome. Transcription factors are members of the proteome as well as regulome.

A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and viruses.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

<span class="mw-page-title-main">Regulation of gene expression</span> Modifying mechanisms used by cells to increase or decrease the production of specific gene products

Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products. Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein. Often, one gene regulator controls another, and so on, in a gene regulatory network.

A transcriptional activator is a protein that increases transcription of a gene or set of genes. Activators are considered to have positive control over gene expression, as they function to promote gene transcription and, in some cases, are required for the transcription of genes to occur. Most activators are DNA-binding proteins that bind to enhancers or promoter-proximal elements. The DNA site bound by the activator is referred to as an "activator-binding site". The part of the activator that makes protein–protein interactions with the general transcription machinery is referred to as an "activating region" or "activation domain".

<span class="mw-page-title-main">Repressor</span> Sort of RNA-binding protein in molecular genetics

In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the promoter, thus preventing transcription of the genes into messenger RNA. An RNA-binding repressor binds to the mRNA and prevents translation of the mRNA into protein. This blocking or reducing of expression is called repression.

<span class="mw-page-title-main">General transcription factor</span> Class of protein transcription factors

General transcription factors (GTFs), also known as basal transcriptional factors, are a class of protein transcription factors that bind to specific sites (promoter) on DNA to activate transcription of genetic information from DNA to messenger RNA. GTFs, RNA polymerase, and the mediator constitute the basic transcriptional apparatus that first bind to the promoter, then start transcription. GTFs are also intimately involved in the process of gene regulation, and most are required for life.

<span class="mw-page-title-main">Silencer (genetics)</span> Type of DNA sequence

In genetics, a silencer is a DNA sequence capable of binding transcription regulation factors, called repressors. DNA contains genes and provides the template to produce messenger RNA (mRNA). That mRNA is then translated into proteins. When a repressor protein binds to the silencer region of DNA, RNA polymerase is prevented from transcribing the DNA sequence into RNA. With transcription blocked, the translation of RNA into proteins is impossible. Thus, silencers prevent genes from being expressed as proteins.

<span class="mw-page-title-main">Regulator gene</span>

A regulator gene, regulator, or regulatory gene is a gene involved in controlling the expression of one or more other genes. Regulatory sequences, which encode regulatory genes, are often at the five prime end (5') to the start site of transcription of the gene they regulate. In addition, these sequences can also be found at the three prime end (3') to the transcription start site. In both cases, whether the regulatory sequence occurs before (5') or after (3') the gene it regulates, the sequence is often many kilobases away from the transcription start site. A regulator gene may encode a protein, or it may work at the level of RNA, as in the case of genes encoding microRNAs. An example of a regulator gene is a gene that codes for a repressor protein that inhibits the activity of an operator.

<span class="mw-page-title-main">MECP2</span> DNA-binding protein involved in methylation

MECP2 is a gene that encodes the protein MECP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in high levels. The MECP2 protein is likely to be involved in turning off several other genes. This prevents the genes from making proteins when they are not needed. Recent work has shown that MECP2 can also activate other genes. The MECP2 gene is located on the long (q) arm of the X chromosome in band 28 ("Xq28"), from base pair 152,808,110 to base pair 152,878,611.

<span class="mw-page-title-main">Coactivator (genetics)</span> Class of proteins involved in regulation of transcription

A coactivator is a type of transcriptional coregulator that binds to an activator to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression. The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.

Cis-regulatory elements (CREs) or Cis-regulatory modules (CRMs) are regions of non-coding DNA which regulate the transcription of neighboring genes. CREs are vital components of genetic regulatory networks, which in turn control morphogenesis, the development of anatomy, and other aspects of embryonic development, studied in evolutionary developmental biology.

An insulator is a type of cis-regulatory element known as a long-range regulatory element. Found in multicellular eukaryotes and working over distances from the promoter element of the target gene, an insulator is typically 300 bp to 2000 bp in length. Insulators contain clustered binding sites for sequence specific DNA-binding proteins and mediate intra- and inter-chromosomal interactions.

<i>trp</i> operon Operon that codes for the components for production of tryptophan

The trp operon is a group of genes that are transcribed together, encoding the enzymes that produce the amino acid tryptophan in bacteria. The trp operon was first characterized in Escherichia coli, and it has since been discovered in many other bacteria. The operon is regulated so that, when tryptophan is present in the environment, the genes for tryptophan synthesis are repressed.

<span class="mw-page-title-main">CTCF</span> Transcription factor

Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the CTCF gene. CTCF is involved in many cellular processes, including transcriptional regulation, insulator activity, V(D)J recombination and regulation of chromatin architecture.

<span class="mw-page-title-main">Eukaryotic transcription</span> Transcription is heterocatalytic function of DNA

Eukaryotic transcription is the elaborate process that eukaryotic cells use to copy genetic information stored in DNA into units of transportable complementary RNA replica. Gene transcription occurs in both eukaryotic and prokaryotic cells. Unlike prokaryotic RNA polymerase that initiates the transcription of all different types of RNA, RNA polymerase in eukaryotes comes in three variations, each translating a different type of gene. A eukaryotic cell has a nucleus that separates the processes of transcription and translation. Eukaryotic transcription occurs within the nucleus where DNA is packaged into nucleosomes and higher order chromatin structures. The complexity of the eukaryotic genome necessitates a great variety and complexity of gene expression control.

Cellular memory modules are a form of epigenetic inheritance that allow cells to maintain their original identity after a series of cell divisions and developmental processes. Cellular memory modules implement these preserved characteristics into transferred environments through transcriptional memory. Cellular memory modules are primarily found in Drosophila.

Epigenetics of human development is the study of how epigenetics effects human development.

References

  1. ↑ Lewis, Mitchell (June 2005). "The lac repressor". Comptes Rendus Biologies. 328 (6): 521–548. doi:10.1016/j.crvi.2005.04.004. ISSN   1631-0691. PMID   15950160.
  2. ↑ Urnov, F. D.; Wolffe, A. P. (2001-05-28). "Chromatin remodeling and transcriptional activation: the cast (in order of appearance)". Oncogene. 20 (24): 2991–3006. doi: 10.1038/sj.onc.1204323 . ISSN   0950-9232. PMID   11420714.
  3. 1 2 Shingler, V. (February 1996). "Signal sensing by sigma 54-dependent regulators: derepression as a control mechanism". Molecular Microbiology. 19 (3): 409–416. doi: 10.1046/j.1365-2958.1996.388920.x . ISSN   0950-382X. PMID   8830233. S2CID   19365107.
  4. ↑ McManus, Michael T.; Petersen, Christian P.; Haines, Brian B.; Chen, Jianzhu; Sharp, Phillip A. (June 2002). "Gene silencing using micro-RNA designed hairpins". RNA. 8 (6): 842–850. doi:10.1017/s1355838202024032. ISSN   1355-8382. PMC   1370301 . PMID   12088155.
  5. ↑ Ho, T; Yap, NL; Roberts, R; Stewart, AF (2012). "Mechanisms of Translational Derepression During Ischemia". Canadian Journal of Cardiology. 28 (5): S193–S194. doi:10.1016/j.cjca.2012.07.256.
  6. ↑ Rogg, L. E.; Bartel, B. (November 2001). "Auxin signaling: derepression through regulated proteolysis". Developmental Cell. 1 (5): 595–604. doi: 10.1016/s1534-5807(01)00077-6 . ISSN   1534-5807. PMID   11709180.
  7. ↑ Delker, Carolin; Raschke, Anja; Quint, Marcel (April 2008). "Auxin dynamics: the dazzling complexity of a small molecule's message". Planta. 227 (5): 929–941. doi:10.1007/s00425-008-0710-8. ISSN   0032-0935. PMID   18299888. S2CID   27623581.
  8. 1 2 3 4 Gabellini, Davide; Green, Michael R.; Tupler, Rossella (June 2004). "When enough is enough: genetic diseases associated with transcriptional derepression". Current Opinion in Genetics & Development. 14 (3): 301–307. doi: 10.1016/j.gde.2004.04.010 . ISSN   0959-437X. PMID   15172674.
  9. 1 2 3 Gabellini, Davide; Tupler, Rossella; Green, Michael R. (June 2003). "Transcriptional derepression as a cause of genetic diseases". Current Opinion in Genetics & Development. 13 (3): 239–245. doi:10.1016/s0959-437x(03)00050-9. ISSN   0959-437X. PMID   12787785.
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